Substituted pyrrolobenzimidazoles for treating inflammatory diseases

• US 6,147,096 A
• Filed: 02/25/1999
• Issued: 11/14/2000
• Est. Priority Date: 02/26/1998
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Dodd, John H., Rupert, Kenneth C., Henry, James R.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US09/257,121
• Time in Patent Office: 628 Days
• Field of Search: 546/273.1, 546/256, 514/338, 514/333
• US Class Current: 514/338
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

This invention provides compounds, and pharmaceutically acceptable salts thereof, having the structure shown below, as well as related pharmaceutical compositions, and methods of treatment and synthesis. ##STR1##

Claims

1. A compound having the structure ##STR16## or a pharmaceutically acceptable salt thereof, wherein:

(a) R₁, R₂ and R₃ are independently selected from the group consisting of (i) hydrogen, (ii) C_1-5 alkyl, (iii) C_1-5 alkylamino, (iv) diC_1-5 alkylamino, (v) a phenyl substituted with one or more of hydrogen, halogen, C_1-5 alkyl, and trihaloC_1-5 alkyl, and (vi) a phenylC_1-5 alkyl substituted with one or more of hydrogen, halogen, C_1-5 alkyl, and trihaloC_1-5 alkyl;

(b) rings 1 and 2 are each independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C_1-5 alkyl, and trihaloC_1-5 alkyl;

(c) A and B are independently nitrogen or carbon, at least one of A and B being nitrogen;

(d) D and E are nitrogen, with the proviso that (i) a double bond exists between the non-aryl carbon and either D or E, (ii) R₂ is absent if the double bond exists between the non-aryl carbon and D, and (iii) R₃ is absent if the double bond exists between the non-aryl carbon and E; and

(e) the compound is neither 1,6-dihydro-7-(4-pyridyl)-8-(4-fluorophenyl)-2-phenylmethyl-pyrrolo[3,2-e]benzimidazole, nor 3,6-dihydro-8-(4-fluorophenyl)-3-(3-phenylpropyl)-7-(4-pyridyl)-pyrrolo[3,2-e]benzimidazole.

2. The compound of claim 1, wherein A is nitrogen and B is carbon.

3. The compound of claim 1, wherein D, E and A are nitrogen and B is carbon.

4. The compound of claim 1, wherein the compound is 1,6-dihydro-7-(4-fluorophenyl)-8-(4-pyridyl)-2-phenyl-pyrrolo[3,2-e]benzimidazole.

5. The compound of claim 1, wherein the compound is 1,6-dihydro-7-(4-fluorophenyl)-8-(4-pyridyl)-2-butyl-pyrrolo[3,2-e]benzimidazole.

6. The compound of claim 1, wherein the compound is 1,6-dihydro-7-(4-fluorophenyl)-8-(4-pyridyl)-2-(2-phenylethyl)-pyrrolo[3,2-e]benzimidazole.

7. The compound of claim 1, wherein the compound is 1,6-dihydro-7-(4-pyridyl)-8-(4-fluorophenyl)-pyrrolo[3,2-e]benzimidazole.

8. The compound of claim 1, wherein the compound is 1,6-dihydro-7-(4-fluorophenyl)-8-(4-pyridyl)-2-phenylmethyl-pyrrolo[3,2-e]benzimidazole.

9. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.

10. A method of treating a subject having an inflammatory disease, which comprises administering to the subject a therapeutically effective dose of the pharmaceutical composition of claim 9.

11. The method of claim 10, wherein the disease is selected from the group consisting of rheumatoid arthritis, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn'"'"'s disease, autoimmune nephritis, primary biliary cirrhosis and psoriasis, acute pancreatitis, allograph rejection, allergic inflammation, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, and cognitive deficits induced by neuronal inflammation.

12. The method of claim 11, wherein the disease is rheumatoid arthritis.